New piperidine tetrahydropyridine and pyrrolidine compounds

ABSTRACT

The invention relates to compounds of formula I: ##STR1## in which R 1  represents a naphthyl radical, a dihydronaphthyl radical, a tetrahydronaphthyl radical, a quinolyl radical or a 1,4-benzodioxanyl radical, A represents a single bond, a double bond, a methylene radical, a radical of formula z 1  : 
     
         --CH═                                                  (z.sub.1) 
    
     or a radical of formula z 2  : 
     
         ═CH--                                                  (z.sub.2) 
    
     the ring B represents a piperidyl radical, a pyrrolidinyl radical, or a 1,2,3,6-tetrahydropyridyl radical, and R 2  represents: a hydrogen atom, a benzyl radical, or an alkyl radical having 1 to 6 carbon atoms, on condition that in one of these cases R 1  is other than a naphthyl (y 1 ), dihydronaphthyl (y 2 ) or tetrahydronaphthyl (y 3 ) radical and B is other than a piperidinyl radical, or an aminoalkyl radical having 1 to 6 carbon atoms, a cyanoalkyl radical having 1 to 6 carbon atoms, or a radical of formula w 1  : ##STR2## in which n is 1-6 and R 4  represents a hydrogen atom, a halogen atom, an alkyl radical having 1 to 6 carbon atoms, or an alkoxy radical having 1 to 6 carbon atoms , and their addition salts with a pharmaceutically-acceptable inorganic or organic acid, and medicaments containing the same.

The present invention relates to new piperidine, tetrahydropyridine andpyrrolidine compounds.

Some 4-naphth-1-yl-1,2,3,6-tetrahydropyridine compounds having antiviralproperties are described in the literature (EP 156,433).

4-(3,4-Dihydro-2-phenyl-1-napth-1-yl)piperidine compounds havingcontraceptive or sedative properties are also known (J. Med. Chem.(1967), 10(1), pp 78-84 Arzneim. Forsch., (1970), 20(9), pp 1235-1238 ;Int. J. Neuropharmacol. (1969), 8(2) pp 153-160) Acta. Pol. Pharm.(1967), Vol 24(5), pp 489-96 ; J.Chem. Soc. C. (1969) 2 pp 217-22).

Trifluoromethylphenyltetrahydropyridines are also used for thepreparation of medicaments intended to control anxiety-depressiondisorders.

The compounds of the invention are distinguished from other piperidine,tetrahydropyridine and pyrrolidine compounds described in the literatureand mentioned above by their original structures and by theirpharmacological properties.

On the cardiovascular level, the compounds of the invention reduce thearterial pressure and the heart rate. This action results from a centralinhibition of the sympathetic tonus and is associated with their5-HT_(1A) agonist properties.

At the level of the central nervous system, the compounds Of theinvention have demonstrated 5-HT_(1A) agonist properties.

They may therefore be useful in the treatment of hypertension, migraine,depression, anxiety, schizophrenia, stress and pain.

DESCRIPTION OF THE DRAWINGS

In the drawings, FIG. 1 is a graph and an amplified graph showingsympathetic nervous activity (SNA) as demonstrated for compounds of theinvention according to Example 34.

The present invention relates more particularly to the compounds ofgeneral formula I: ##STR3## in which R₁ represents a naphthyl radical,of formula y₁ : a dihydronaphthyl radical, of formula y₂ : ##STR4## atetrahydronaphthyl radical of formula y₃ : ##STR5## in which formulae R₃represents a hydrogen atom, a halogen atom, an alkyl radical having 1 to6 carbon atoms, a hydroxyl radical or an alkoxy radical having 1 to 6carbon atoms), a quinol-3-yl radical (optionally substituted on thebenzene ring by one or more halogen atoms, alkyl radicals having 1 to 6carbon atoms, hydroxyl radicals or alkoxy radicals having 1 to 6 carbonatoms) or a 1,4-benzodioxan-5-yl radical,

A represents a single bond, a double bond (on condition, however, thatR₁ represents a tetrahydronaphthyl radical), a methylene radical, aradical of formula z₁ :

    --CH═                                                  (z.sub.1)

or a radical of formula z₂ : (on condition, however, that in this caseR₁ represents a tetrahydronaphthyl radical),

    ═CH-- (z.sub.2)

the ring B represents a piperidyl radical (on condition, however, thatin this case A represents a single or a double bond), a pyrrolidinylradical (on condition, however, that in this case A represents amethylene radical, a radical z₁ or a radical z₂) or a1,2,3,6-tetrahydropyridyl radical (on condition, however, that in thiscase A represents a single bond), and

R₂ represents:

a hydrogen atom, a benzyl radical or an alkyl radical having 1 to 6carbon atoms, on condition that in one of these cases R₁ is other than anaphthyl (y₁), dihydronaphthyl (y₂) or tetrahydronaphthyl (y₃) radicaland B is other than a piperidinyl radical, or

an aminoalkyl radical having 1 to 6 carbon atoms, a cyanoalkyl radicalhaving 1 to 6 carbon atoms or a radical of formula w₁ : ##STR6## (inwhich: n is 1-6 and

R₄ represents a hydrogen atom, a halogen atom, an alkyl radical having 1to 6 carbon atoms or an alkoxy radical having 1 to 6 carbon atoms),

on condition, however, that

when R₁ is a radical y₂, R₃ represents a hydrogen atom, A a single bondand B a piperidyl radical, R₂ does not at the same time represent amethyl radical, and

when R₂ is a radical y₁, R₃ represents a hydrogen atom, A a single bondand B a 1,2,3,6-tetrahydropyridyl radical, R₂ does not at the same timerepresent a hydrogen atom, and

when R₁ is a radical y₃, R₃ represents a hydrogen atom, A a double bondand B a piperidyl radical, R₂ does not at the same time represent amethyl radical,

its possible stereoisomers,

and its addition salts with a pharmaceutically acceptable inorganic ororganic acid.

The present invention also relates to a process for preparing compoundsof general formula I, wherein: either

a compound of formula II: ##STR7## in which R_(2') represents an alkylradical having 1 to 6 carbon atoms or a benzyl radical, is reacted witha compound of formula III:

    R.sub.1 --X                                                (III)

in which R₁ has the same meaning as for the formula I and X represents abromine or lithium atom or an MgBr group, to form the compounds offormula IV: ##STR8## in which R₁ has the meaning indicated above andR_(2') represents an alkyl radical having 1 to 6 carbon atoms or abenzyl radical,

which is subjected to the action of hydrobromic acid to form thecompounds of formula I_(a) : ##STR9## in which R₁ has the same meaningas for the formula I and R_(2') represents an alkyl radical having 1 to6 carbon atoms or a benzyl radical, and then

either

the compounds of formula I_(a) are subjected to the action of ethylchloroformate in the presence of an alkali metal inorganic salt to formthe compounds of formula V: ##STR10## in which R₁ has the same meaningas for the formula I, A is a single bond and B represents a1,2,3,6-tetrahydropyridyl radical,

or

the compounds of formula Ia are first subjected to a catalytichydrogenation to form the compounds of formula I_(b) : ##STR11## inwhich R₁ has the same meaning as for the formula I and R_(2') representsan alkyl radical having 1 to 6 carbon atoms or a benzyl radical,

then to the action of ethyl chloroformate in the presence of an alkalimetal inorganic salt to form the compounds of formula V,

in which R₁ has the same meaning as for the formula I and B represents apiperidyl radical, or

a compound of formula VI: ##STR12## in which R₃ has the same meaning asfor the formula I, is reacted either

with a compound of formula VII, ##STR13## to form the compounds offormula V in which R₁ represents a tetrahydronaphthyl radical of formulay₃, A is a double bond and B represents a piperidyl radical,

or

with a compound of formula VIII: ##STR14## in which R_(2') has the samemeaning as for the formula II, to form the compounds of formula IX:##STR15## in which the meaning of R₃ and R_(2') remains identical tothat given above,

which are subjected to the action of paratoluenesulfonic acid to formthe compounds of formulae I_(c) and I_(d) : ##STR16## in which formulaeR₃ has the same meaning as for the formula I and the meaning of R_(2')is identical to that given for the formula II, which compounds are thenseparated

then subjected to the action of ethyl chloroformate in the presence ofan alkali metal inorganic salt to form the compounds of formula V, inwhich R₁ represents a dihydronaphthyl radical of formula y₂ or atetrahydronaphthyl radical of formula y₃, A is, respectively, amethylene radical or a radical of formula z₂ and B represents apyrrolidinyl radical, or

with a compound of formula X: ##STR17## in which R_(2') has the samemeaning as for the formula II, to form the compounds of formula XI:##STR18## in which the meaning of R₃ remains identical to that given forthe formula I and R_(2') represents a benzyl radical or an alkyl radicalhaving 1 to 6 carbon atoms,

which compounds are then subjected to the action of para-toluenesulfonicacid to form the compounds of formula I_(e) : ##STR19## in which R₃ hasthe same meaning as for the formula I and R_(2') represents an alkylradical having 1 to 6 carbon atoms or a benzyl radical, which compoundsare then

either

reacted with ethyl chloroformate to form the compounds of formula V inwhich R₁ represents a dihydronaphthyl radical of formula y₂, A is asingle bond and B represents a piperidyl radical,

or

subjected to the action of tetrachloro-1,2-benzoquinone to form thecompounds of formula I_(f) : ##STR20## in which R₃ has the same meaningas for the formula I and R_(2') represents an alkyl radical having 1 to6 carbon atoms or a benzyl radical,

which compounds are then

reacted with ethyl chloroformate to form the compounds of formula V inwhich R₁ represents a naphthyl radical of formula y₁, A is a single bondand B represents a piperidyl radical,

and then

the compounds of formula V are subjected either to the action ofhydrobromic acid or to the action of potassium hydroxide, to form thecompounds of formula Ig: ##STR21## in which the meaning of R₁, A and Bremains identical to that given for the formula I,

which compounds are then reacted with a compound of formula XII:

    Br--(CH.sub.2).sub.n -1--CN                                (XII)

in which n has the same meaning as for the formula I, to form thecompounds of formula I_(h) : ##STR22## in which R₁, A, B and n have thesame meaning as for the formula I, which compounds are then subjected tothe action of lithium aluminum hydride to form the compounds of formulaI_(i) : ##STR23## in which the meaning of R₁, A, B and n remainsidentical to that given for the formula I, which compounds are reactedwith a compound of formula XIII: ##STR24## in which the meaning of R₄remains identical to that given for the formula I, to form the compoundsof formula I_(j) : ##STR25## in which R₁, A, B, n and R₄ have the samemeaning as for the formula I, and then

the compounds of formula I_(a) -I_(j) (which make up all of thecompounds of formula I) are separated into their possible stereoisomers,

and/or the said compounds are converted to a salt with apharmaceutically acceptable organic or inorganic acid, to form thecorresponding addition salts.

The reaction of the compounds of formula II with the compounds offormula III is carried out in the presence of butyllithium, intetrahydrofuran or some other chemically equivalent solvent, and at atemperature of between -60° C. and -78° C.

Preferentially, the catalyst used during the hydrogenation of thecompounds of formula I_(a) to form the compounds of formula I_(b) ispalladium-on-charcoal.

During the reaction of the compounds of formulae Ia, I_(b), I_(c),I_(d), I_(e) and I_(f) with ethyl chloroformate, the alkali metalinorganic salt used is sodium bicarbonate.

The reaction of the compounds of formula VI with the compounds offormula VII is carried out in the presence of the titaniumtrichloride/dimethoxyethane complex and the zinc-copper system (preparedby the process described in J.Org.Chem. (1989), 54, p. 3749).

The reaction of the compounds of formula IX and XI withpara-toluenesulfonic acid is carried out at elevated temperature, indichloromethane or in some other halogenated aliphatic solvent of lowmolecular weight (C₁ -C₃).

In order to form the compounds of formula I_(f), the oxidation of thecompounds of formula Ie is carried out usingtetrachloro-1,2-benzoquinone, at elevated temperature, in an anhydrousalcoholic solvent.

In order to form the compounds of formula I_(g), the compounds offormula V are subjected at elevated temperature either to the action ofpotassium hydroxide in solution in ethanol or to the action of 48%hydrobromic acid.

The reaction of the compounds of formula I_(i) with the compounds offormula XIII is carried out at ambient temperature.

Amongst the pharmaceutically acceptable acids for the preparation of theaddition salts with compounds of general formula I, the following may bementioned: hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric,ascorbic, tartaric, maleic, mandelic and methanesulfonic acids, etc.

The compounds of the present invention have very valuablepharmacological properties. On the cardiovascular level, the compoundsof the invention lower the arterial pressure and the heart rate in ratsand in dogs. This action results from a central inhibition of thesympathetic tonus. In fact, pharmacological studies have shown that thelowering in pressure caused by the i.v. administration of the compoundsof the invention to dogs is accompanied by a significant reduction inthe electrical activity of the renal sympathetic nerve.

This central reduction in the sympathetic tonus results from anactivation Of the central 5-HT_(1A) receptors at the level of theretrofacial nucleus (Eur. Journal of Pharm., (1989,160,p.385-294).Pharmacological studies have also proved that the compounds of theinvention are more active than flesinoxan, a reference compound havingantihypertensive properties owing to its agonist activity on the5-HT_(1A) receptors (European Journal of Pharmacology,(1988),149,p.213-223). On the other hand, the compounds of the inventionhave a beneficial activity at the renal level (T.I.P.S., (1989), 10,p.469-471).

Binding studies have confirmed that the compounds of the invention alsobehave as very powerful ligands for 5-HT_(1A) receptors, with an agonistor antagonist activity on the central nervous system.

The compounds of the invention therefore find their application in thetreatment of stress (Neuropharmac.,(1989), Vol.25, No.5, p.471-476),migraine (T.I.P.S., (1989), Vol.10, pp.200-204) anxiety, depression,schizophrenia and pain (Pharmacology and Toxicology, (1989), 64, p.3-5),(Drugs of the Future, (1988), 13, No.5, p.429-437), (J. Neural. Transm.,(1988), 74, p.195-198).

The compounds which are active at the level of the 5-HT_(1A) receptorsmay also modify the alimentary and sexual behavior (Jour. of ReceptorResearch, (1988), 8, p.59-81).

The invention also extends to the pharmaceutical compositionscontaining, as active principle, at least one compound of generalformula I, or one of its salts with a pharmaceutically compatibleinorganic or organic acid, in combination with one or more inert andsuitable excipients.

The pharmaceutical compositions thus obtained are advantageouslypresented in diverse forms, such as, for example, tablets, coatedtablets, capsules, suppositories, injectable solutions or drinkablesolutions.

The dosage may vary widely depending on the age and the weight of thepatient, on the nature and the severity of the illness and on theadministration route. In general, the unit dose will range between 0.1and 100 mg and the daily dose, usable in human medicine, between 0.1 and500 mg. The preferred administration route is the oral or parenteralroute.

The following examples, given without any limitation being implied,illustrate the invention.

The melting points were measured using the Micro-Kofler technique.

The proton nuclear magnetic resonance (1H NMR) spectra of the compoundsof general formula I were recorded, depending on the case, at 200 and400 MHz and are indicated in Table I.

EXAMPLE 1 1-Methyl-4 (naphth-1-yl) 1,2,3,6 tetrahydropyridinehydrobromide Stage A 4-Hydroxy-1 methyl-4-(naphth 1-yl)piperidine

A solution of 51.75 g of 1-bromonaphthalene in 250 ml of tetrahydrofuranis added dropwise, at -78° C. and under a stream of nitrogen, to asolution of 175 ml of butyllithium (1.6 M in hexane) in 500 ml oftetrahydrofuran.

After stirring for 1 hour, a solution of 28.29 g of1-methylpiperid-4-one in 250 ml of tetrahydrofuran is added dropwise.

The reaction mixture is stirred for 1 hour at -78° C. and then for 5hours at 20° C. and is then hydrolyzed with 100 ml of a saturatedammonium chloride solution.

Extraction with dichloromethane followed by evaporation of the solventleaves an oily residue which, taken up in ethyl ether, crystallizes inthe form of a white solid.

Yield: 73 %

Melting point : 160° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 2.2 ppm s+m3H+4H; 2.65 ppm m 4H; 7.35 ppm m 4H; 7.75 ppm d 1H; 7.85 ppm m 1H; 8.9ppm m 1H. Stage B

49 g of the compound obtained in the preceding stage, in suspension in 1liter of a 48% hydrobromic acid solution, are refluxed for 24 hours. Theresidue obtained after evaporation is taken up 3 times with ethanol andthen with acetone to yield, after filtration and drying, 47.94 g of1-methyl-4-naphth-1-yl-1,2,3,6-tetrahydropyridine hydrobromide.

Yield : 86.65%

Melting point : >260° C.

EXAMPLE 2 1 Methyl-4-naphth-1-ylpiperidine hydrobromide

20 g of the compound from Example 1 are reduced with 1680 ml of hydrogenunder atmospheric pressure and at ambient temperature, in the presenceof 1 g of 10% palladium-on-charcoal, in 1 liter of ethanol and 100 ml ofdimethylformamide.

After filtering off the catalyst and evaporation of the solvents, acrude product is obtained which when taken up in acetone yields 19 g ofthe expected hydrobromide.

Yield : 95.5%

Melting point : >260° C.

EXAMPLE 3 4-Naphth-1-ylpiperidine hydrobromide Stage A Ethyl[4-(naphth-1 Yl)piperid-1-yl]carbamate

19 g of the salt obtained in Example 2 are converted to1-methyl-4-naphth-1-ylpiperidine using sodium hydroxide indichloromethane.

The base thus obtained is immediately brought into contact with 10 g ofsodium bicarbonate in 500 ml of toluene, under a stream of nitrogen. 100ml of ethyl chloroformate are added in fractions to the reaction mixtureand the whole is then refluxed for 24 hours. Filtration followed byevaporation leads to 10.7 g of an oil.

Yield: 61.14%

Stage B

10.5 g of the compound obtained in Stage A in 300 ml of a 48%hydrobromic acid solution, are refluxed for 20 hours. After evaporationand washing twice with ethanol, the residue is taken up in acetone andthe mixture then filtered to give 4-(naphth-1-yl)pyperidinehydrobromide.

Yield: 86.64%

Melting point: >260° C.

EXAMPLE 4 (4-Naphth-1-ylpiperid-1-yl)acetonitrile hydrochloride

5 g of the compound from Example 3, 7.088 g of potassium carbonate and2.259 g of bromoacetonitrile in 200 ml of acetone are stirred for 10hours under reflux and a stream of nitrogen. After filtering andevaporation of the filtrate, the residue obtained is treated with anethanolic solution of hydrogen chloride to give 4.5 g of the expectedhydrochloride.

Yield: 91.83%

Melting point: 172° C.

EXAMPLE 5 1-[2-(4-Fluorobenzamido)eth-1-yl]-4-naphth-1-ylpiperidinehydrochloride Stage A 1-(2-Aminoeth-1-yl)-4-naphth-1-ylpiperidine

1.75 g of lithium aluminum hydride are added in fractions under a streamof nitrogen to a solution of 4.4 g of the compound from Example 4 in 150ml of tetrahydrofuran. After stirring for 1 hour, the mixture ishydrolyzed with 1.75 ml of water, 3.5 ml of a 10% (wt/wt) sodiumhydroxide solution and 7 ml of water. Filtration through celite,followed by evaporation of the solvent, yields an oily product which isused as it is in the following stage.

Yield: quantitative

Stage B

A solution of 1.81 g of triethylamine in 40 ml of tetrahydrofuran isadded dropwise at -5° C., under a stream of nitrogen, to a solution of3.8 g of the compound obtained in the preceding stage, in 180 ml oftetrahydrofuran. Under the same conditions, a solution of 2.84 g of4-fluorobenzoyl chloride in 40 ml of tetrahydrofuran is added to thereaction mixture. After having stirred for 1 hour at ambienttemperature, the mixture is hydrolyzed using a saturated sodiumbicarbonate solution. Phase separation, followed by drying of theorganic phase over sodium sulfate and the evaporation of the solventleads to a product which, when taken up in ethyl ether, crystallizes inthe form of a white solid.

3.3 g of the corresponding hydrochloride are obtained after addition ofan ethanolic solution of hydrogen chloride.

Yield: 64%

Melting point: 260° C.

EXAMPLE 61-[2-(4-Fluorobenzamido)eth-1-yl]-4-naphth-1-yl-1,2,3,6-tetrahydropyridinehydrochloride Stage A Ethyl(4-naphth-1-yl-1,2,3,6-tetrahydropyrid-1-yl)carbamate

22.3 g of the compound from Example 1 are treated with 50 ml of ethylchloroformate and 30 g of sodium bicarbonate, in accordance with theprocedure described in Stage A of Example 3, to give the expectedproduct.

Yield: 53.88%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 1.3 ppm t3H; 2.55 ppm m 2H 3.8 ppm m 2H 4.1-4.3 ppm g+m+m 2H+1H+1H; 5.8 ppm m 1H;7.25 ppm dd 1H; 7.35-7.55 ppm m 3H; 7.7-8 ppm 2H+1H.

Stage B 4-Naphth-1-yl-1,2,3,6-tetrahydropyridine hydrobromide

The treatment of 11 g of the carbamate obtained in the preceding stagewith a 48% hydrobromic acid solution yields 9.02 g of4-naphth-1-yl-1,2,3,6-tetrahydropyridine hydro bromide.

Yield: 80%

Melting point: >260° C.

Stage C (4-Naphth-1-yl-1,2,3,6 tetrahydropyrid-1-yl)acetonitrilehydrochloride

This salt was obtained from the compound obtained in Stage B using theprocess described in Example 4.

Yield: 80%

Stage D 1-(2-Aminoeth-1-yl)-4-naphth-1-yl-1,2,3,6-tetrahydropyridine

6.25 g of the hydrochloride prepared previously are reduced using 2.5 gof lithium aluminum hydride and yield the expected amino compound, whichis used immediately in the following stage.

Yield: quantitative

Stage E

The treatment of 5.5 g of the amine prepared in the preceding stage with2.66 g of triethylamine and 4.18 g of 4-fluorobenzoyl chloride leads toa crude product which is purified by chromatography on a silica gelcolumn (70-230 mesh) using a 97: 3: 0.3 (V/V/V) mixture ofdichloromethane, methanol and aqueous ammonia as the elution solvent.

The product thus obtained is converted to the hydrochloride.

Yield: 37%

Melting point: 233° C.

EXAMPLE 7 3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)quinolinedihydrobromide Stage A 3-(4-Hydroxy 1-methylpiperid 4-yl)quinoline

95.01 g of 3-bromoquinoline were treated with 200 ml of a 2.5 M solutionof butyllithium in hexane and 51.62 g of 1-methylpiperid-4-one inaccordance with the procedure described in Stage A of Example 1, inorder to obtain the expected product.

Yield: 53.84%

Melting point: 175° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 2.3 ppm t+d2H; 2.4 ppm s 3H; 2.55 pp t+d 2H; 2.85 ppm d 2H; 7.7 and 7.55 ppm m+m2H; 7.8 ppm d 1H; 8.10 ppm d 1H; 8.25 ppm d 1H; 9.1 ppm d 1H.

Stage B

The 3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)quinoline dihydrobromidewas obtained by treating 53 g of the compound obtained in Stage A with a48% hydrobromic acid solution.

Yield: 72.80%

Melting point: >260° C.

EXAMPLE 8 3-(1,2,3,6-Tetrahydropyrid-4-yl)quinoline hydrochloride

This product was prepared from the compound of Example 7 and using theprocedure described in Stages A and B of Example 6. The compoundobtained was converted to a salt using an alcoholic solution of hydrogenchloride.

Yield: 65%

Melting point: >260° C.

EXAMPLE 9 3-(1-Methylpiperid-4-yl)quinoline dihydrobromide

Hydrogenation of the compound of Example 7, in accordance with theprocedure described in Example 2, yields the expected compound.

Yield: 95.4%

Melting point: >260° C.

EXAMPLE 10 3-Piperid-4-ylquinoline dihydrobromide

This product was prepared from the compound of Example 9 using theprocedure described in Example 3.

Yield: 74%

Melting point: >260° C.

EXAMPLE 11 [4-(Quinol-3-yl)piperid-1-yl]acetonitrile dihydrochloride

The treatment of 10.90 g of the compound from Example 10 with 2.3 ml ofbromoacetonitrile and 16 g of potassium carbonate yields 9.08 g of theexpected product, in the form of the base. An ethanolic solution ofhydrogen chloride is used for conversion to the salt.

Yield: 85.77%

Melting point: 210°-214° C.

EXAMPLE 12 1-[2-(4-Fluorobenzamido)eth-1-yl]-4-quinol-3-ylpiperidinedihydrochloride

This product was prepared from the compound of Example 11 and inaccordance with the procedure described in Example 5.

Yield: 50%

Melting point: 229° C.

EXAMPLE 131-Benzyl-3-[3,4-dihydro-7-methoxynaphth-1-yl)methylenyl]pyrrolidineStage A1-Benzyl-3-[(1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)methylenyl]pyrrolidine

40 g of 3-chloromethyl-1-benzyl pyrrolidine are added under nitrogen toa suspension of 4.63 g of magnesium in 100 ml of anhydrous ethyl ether.

The reaction mixture is diluted little by little with 300 ml of benzeneat the rate at which the magnesium disappears. The mixture is refluxedfor 1 hour and then cooled to 0° C. and a solution of 37 g of7-methoxy-1,2,3,4-tetrahydronaphth-1-one in 120 ml of benzene is added.

The temperature is allowed to rise to 20° C. and after 36 hours themixture is hydrolyzed with 200 ml of a saturated ammonium chloridesolution.

After drying and concentrating the organic phase, the oil obtained ispurified by chromatography on silica using a 100 3 (V/V) mixture ofdichloromethane and methanol as eluent.

Yield: 48%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 1.65 to 2.1ppm m+m+m+d+dd 1H+2H+2H+2H+1H; 2.15 to 2.5 ppm m+m+m 1H+1H+1H; 2.6 to2.85 ppm m+m+dd 2H+1H+1H; 3.55 ppm dd 2H; 3.75 ppm s 3H; 6.7 ppm dd 1H;7.0 ppm d 1H; 7.05 ppm d 1H; 7.1 to 7.4 ppm m 5H.

Stage B

A solution of 20 g of the product obtained in Stage A and 11.9 g ofpara-toluenesulfonic acid monohydrate in 600 ml of dichloromethane isrefluxed for 30 minutes.

The amine is then salted out using a sodium hydroxide solution and theorganic phase is concentrated. The oil obtained is purified bychromatography on silica (70-230 mesh) using a 3:100 (V/V) mixture ofmethanol and dichloromethane as eluent.

12 g of 1-benzyl-3-[3,4-dihydro-7-methoxynaphth-1-yl)methylenyl]pyrrolidine are thus obtained.

EXAMPLE 14 1-Benzyl-3-[(7 methoxy-1,2,3,4-tetrahydronaphth-1-yl)methylidyn]pyrrolidine

3 g of this compound were obtained on purification, by chromatography,of the oil obtained in Stage B of Example 13.

EXAMPLE 15 4-(3,4-Dihydro-7-methoxynaphth-1-yl)-1 methylpiperidine StageA4-(1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)-1-methylpiperidine

A solution of 40 g of 4-chloro-1-methylpiperidine in 150 ml oftetrahydrofuran is added to a suspension of 6.9 g of magnesium in 50 mlof tetrahydrofuran.

The formation of the magnesium compound is completed by refluxing for 2hours.

A solution of 32.2 g of 7-methoxy-1,2,3,4-tetrahydronaphth-1-one in 150ml of tetrahydrofuran is then added at 10° C.

Stirring of the reaction mixture is continued at ambient temperature for15 hours and the mixture is then hydrolyzed at 0° C. using 15 g ofammonium chloride in solution in 80 ml of water.

After evaporation of the solvent under vacuum, the residue is taken upin water, the mixture is acidified and washed with ethyl ether, theaqueous phase is then rendered alkaline and the product extracted with400 ml of toluene is washed with 200 ml of water.

After concentration under vacuum, the oil obtained crystallizes.

Melting point: >60° C.

Stage B

A solution of 15 g of the oil obtained in Stage A, in 400 ml ofanhydrous dichloromethane, is refluxed for 20 minutes in the presence of11.4 g of para-toluenesulfonic acid.

After cooling, the reaction mixture is washed with 20 ml of a saturatedsodium bicarbonate solution. The organic phase is dried over sodiumsulfate and then concentrated under vacuum. An oil is obtained.

Yield: 40%

EXAMPLE 16 4-(7-Methoxynaphth-1-yl)-1-methylpiperidine

A mixture of 11.5 g of the product from Example 15 and 23.1 g oftetrachloro-1,2-benzoquinone in solution in 600 ml of anhydrous ethylalcohol is refluxed for 30 hours.

After concentration under vacuum, the residue is taken up in water andthen extracted with dichloromethane and the extract is dried overanhydrous sodium sulfate and concentrated under vacuum.

The product obtained is purified on a neutral alumina column using a99.5:0.5 (V/V) mixture of dichloromethane and methanol.

Yield: 82%

EXAMPLE 17 4-(7-Methoxynaphth-1-yl)piperidine hydrochloride Stage AEthyl 4-(7-methoxynaphth-1-yl)piperid-1-yl]carbamate

The compound of Example 16 is dissolved in 200 ml of anhydrous xylene inthe presence of 3.9 g of sodium carbonate and 17.6 ml of ethylchloroformate are added at 20° C. The mixture is refluxed for 24 hours.

The reaction mixture is cooled and then hydrolyzed using a 2 Nhydrochloric acid solution.

The organic phase is washed with a dilute sodium hydroxide solution,dried over sodium sulfate and concentrated under vacuum.

Yield: 88%

Stage B

A mixture of 8.9 g of the carbamate obtained in Stage A, 12.7 g ofpotassium hydroxide, 30 ml of water and 200 ml of ethyl alcohol isrefluxed for 40 hours.

After evaporation under vacuum, the residue is taken up in water and themixture is extracted with dichloromethane.

The organic phase is dried over sodium sulfate and concentrated undervacuum.

The oil obtained is converted to the salt using 3.12 ml of a 7.6 Nethanolic solution of hydrogen chloride.

Yield: 55%

Melting point: 240° C.

EXAMPLE 18 1-[2-(4-Fluorobenzamido)eth-1-yl]-4-(7-methoxynaphth-1-yl)piperidine hydrochloride

This product was prepared from the compound of Example 17 and usingsuccessively the procedures described in Examples 4 and 5.

Yield: 25%

Melting point: 215° C.

EXAMPLE 19 4-(7-Methoxy-1,2,3,4 tetrahydronaphth-1-yl)piperid-4-ylideneStage A Ethyl[4-(7-methoxy-1,2,3,4-tetrahydronaphth-1-y1)piperid-4-ylidene]carbamate

921 g of the 1 M 1.5 M titanium trichloride/dimethoxyethane complex andthen 888 g of the zinc/copper system (prepared by the process describedby J. McMurry. J. Org. Chem. (1989), 54, p. 3749) are pouredsuccessively, under a stream of argon, into 8 liters of dimethoxyethane.The mixture is refluxed for 13 hours and then cooled to 20° C.

A solution consisting of 31 g of7-methoxy-1,2,3,4-tetrahydronaphth-1-one, 60.3 g of ethyl(4-oxopiperid-1-yl)carbamate and 400 ml of dimethoxyethane is addeddropwise in the course of 5 hours to the reaction mixture. The latter isthen refluxed again for 15 hours, then cooled and diluted with 3 litersof dichloromethane.

After filtering through celite and concentrating the filtrate undervacuum, the residue obtained is taken up in 800 ml of dichloromethane.

The insoluble matter is removed by filtering off and the organic phaseis evaporated under vacuum.

The oil obtained is purified by chromatography on a silica column usingdichloromethane as eluent.

Yield: 55%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 1.25 ppm t3H; 1.75 ppm q 2H; 2.45 ppm m 4H; 2.6 ppm t 2H; 2.65 ppm t 2H; 3.4 ppm t2H; 3.55 ppm t 2H; 3.8 ppm s 3H; 4.2 ppm q 2H; 6.7 ppm m 2H; 7.0 ppm d1H.

Stage B

2.6 g of the compound obtained in Stage A were treated by the proceduredescribed in Stage B of Example 17 in order to obtain the expected salt.

Yield: 63%

Melting point: >260° C.

EXAMPLE 20 [4-(7Methoxy-1,2,3,4-tetrahydronaphth-1-yl)piperid-4-ylidene]acetonitrile

This compound was prepared from the compound of Example 19 using theprocedure described in Example 4.

Yield: 94%

EXAMPLE 211-[2-(4-Fluorobenzamido)eth-1-yl]-4-(7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)piperid-4-ylidenehydrochloride

This compound was prepared from the compound of Example 20 using theprocedure described in Example 5.

Yield: 80%

Melting point: 120° C.

EXAMPLE 22 1-Benzyl-4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridineStage A 1-Benzyl-4-hydroxy-4-(1,4-benzodioxan-5-yl)piperidine

23.3 ml of a 1.6 M solution of butyllithium in hexane are added dropwiseto a solution, previously cooled to -60° C., of 8 g of5-bromo-1,4-benzodioxane in 400 ml of tetrahydrofuran. When the additionis complete, the mixture is stirred at -60° C. for 5 minutes and asolution of 8 g of 1-benzylpiperid-4-one in 100 ml of tetrahydrofuran isthen added dropwise. The mixture is stirred for 2 hours at -40° C. andthen for 2 hours at ambient temperature before hydrolyzing using 80 mlof water.

The organic phase is separated off and the aqueous phase is extractedwith twice 100 ml of dichloromethane. The combined organic phases arewashed once using 20 ml of water and dried over magnesium sulfate.

The solvents are evaporated under vacuum and the product obtained in thecrude stage is chromatographed on 520 of silica (70-230 mesh), elutingusing a 98:2 (V/V) dichloromethane/methanol mixture.

Yield: 72%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 2.05 ppm m2H; 2.1 ppm m 2H; 2.55 ppm m 2H; 2.75 ppm m 2H; 3.6 ppm s 2H; 4.25 ppm m4H; 6.8 ppm m 3H; 7.1-7.4 ppm m 5H

Stage B

A solution of 8 g of the product obtained in the preceding stage, in 100ml of glacial acetic acid and 8 ml of concentrated hydrochloric acid, isrefluxed for 14 hours.

After returning to ambient temperature, the mixture is concentrated andthe residue is taken up using 250 ml of dichloromethane.

The separated organic phase is washed once using 80 ml of 1 N sodiumhydroxide and then once using 80 ml of water.

After drying over magnesium sulfate and concentrating under vacuum, anoil is obtained.

Yield: 74%

EXAMPLE 234-[5-(1,4-Benzodioxan-5-yl)]-1-[2-(4-fluorobenzamido)eth-1-yl]-1,2,3,6-tetrahydropyridinehydrochloride Stage A Ethyl[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyrid-1-yl]carbamate

8 g of ethyl chloroformate are added at ambient temperature, withstirring, to a solution containing 5.5 g of the product from Example 22in 50 ml of toluene. When the addition is complete, the mixture isrefluxed for 2 hours.

The cooled solution is filtered, the filtrate is concentrated undervacuum and the residue is taken up in 250 ml of a 50:50 (V/V) mixture ofethyl ether and diisopropyl ether. The precipitate is filtered off andthe filtrate is concentrated in order to obtain an oil.

Yield: 63%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃):

1.3 ppm t 3H; 2.5 ppm m 2H; 3.65 m 2H; 4-4.30 ppm m 2H; 4.10 ppm s 4H;4.35 ppm q 2H; 5.8 ppm m 1H; 6.6-6.8 ppm m 3H

Stage B 4-[(1,4-Benzodioxan-5-yl)]-1,2,3,6-tetrahydropyridinehydrochloride

1.7 ml of trimethylsilane iodide are added dropwise to a solution of 3 gof the carbamate obtained in the preceding stage, in 4.2 ml ofchloroform. When the addition is complete, the mixture is stirred for 1hour under reflux and then for 2 hours at ambient temperature.

The mixture is filtered rapidly, the filtrate is diluted using 20 ml ofchloroform, 10 ml of a methanolic solution of hydrogen chloride are thenadded dropwise and the mixture is diluted using 30 ml of ethyl ether.The precipitate formed is the expected product.

Yield: 77%

Melting point: 184° C. (decomposition)

Stage C[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyrid-1-yl]acetonitrile

2.5 g of potassium carbonate and, dropwise, a solution of 1.08 g ofbromoacetonitrile in 10 ml of acetone are added to a solution of 1.9 gof the amine hydrochloride obtained in Stage B in 40 ml of acetone.

The mixture is stirred for 2 hours at ambient temperature and filteredand the filtrate is concentrated under vacuum. The residue, taken up in20 ml of dichloromethane, is washed using 10 ml of water and the organicphase is then dried over magnesium sulfate.

After evaporation of the solvent, an oil is obtained.

Yield: 99%

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 2.6 ppm m2H; 2.8 ppm t 2H; 3.3 ppm m 2H; 3.65 ppm s 2H; 4.2 ppm s 4H; 5.8 ppm m1H; 6.75 ppm m 3H

Stage D1-(2-Aminoethyl)-4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine

A solution containing 1.9 g of the compound obtained in Stage C, in 20ml of anhydrous tetrahydrofuran, is added dropwise to a suspension of0.56 g of lithium aluminum hydride in 30 ml of anhydroustetrahydrofuran.

After 4 hours' contact at ambient temperature, the mixture is hydrolyzedusing 0.6 ml of a saturated ammonium chloride solution.

The mixture is filtered and the filtrate is dried over magnesiumsulfate.

After concentration of the solvent, an oil is obtained which is used assuch in the following step.

Stage E

All of the compound obtained in Stage D is dissolved in 20 ml ofchloroform. A solution of 0.64 g of triethylamine in 5 ml of chloroformand then, dropwise, a solution of 0.94 g of para-fluorobenzoyl chloridein 30 ml of chloroform are added thereto.

After 3 hours' contact, the mixture is washed once using 10 ml of waterand the organic phase is dried over magnesium sulfate and thenconcentrated under vacuum.

The crude oil is dissolved in 50 ml of ether and the product isprecipitated by adding an ethereal solution of hydrogen chloride.

The precipitate filtered off is taken up in 20 ml of ether. A solid isthus obtained which is the expected salt.

Yield: 68%

Melting point: 214° C.

EXAMPLE 24[4-(3,4-Dihydro-7-methoxynaphth-1-yl)piperid-1-yl]acetonitrile Stage AEthyl[4-(3,4-dihydro-7-methoxynaphth-1-yl)piperid-1-yl]carbamate

The expected product is obtained using the compound from Example 15 andtreating it in accordance with the procedure described in Stage A ofExample 3.

Yield: 93%

Stage B 4-(3,4-Dihydro-7-methoxynaphth-1-yl)piperidine

The expected product is obtained using the compound described in Stage Aand treating it in accordance with the procedure described in Stage B ofExample 17.

Yield: 77%

Stage C [4-(3,4-Dihydro-7-methoxynaphth-1-yl]piperid-1yl]acetonitrile

The expected product is obtained using the compound described in Stage Band treating it in accordance with the procedure described in Example 4.

Yield: 92%

    ______________________________________                                        Elementary microanalysis:                                                              C %        H %    N %                                                ______________________________________                                        Calculated 76.56        7.85   7.79                                           Found      75.50        9.92   9.57                                           ______________________________________                                    

EXAMPLE 25 1-(2-Aminoeth-1-yl)-4-(3,4-dihydro-7-methoxynaphth-1-yl)piperidine

The expected product is obtained using the compound from Example 24 andtreating it in accordance with the process described in Stage A ofExample 5.

Yield: 81%

EXAMPLE 26 1-(2-Aminoeth 1-yl)4-(1,2,3,4-tetrahydro-7-methoxynaphth-1-yl)piperidine

900 mg of the compound described in Example 25 are reduced by catalytichydrogenation at ambient temperature in the presence of 0.1 g ofplatinum oxide in 10 ml of acetic acid. The expected product is obtainedafter filtering off the catalyst, neutralizing the filtrate with sodiumhydroxide solution and extracting with dichloromethane.

Yield: =100%

    ______________________________________                                        Elementary microanalysis:                                                              C %        H %    N %                                                ______________________________________                                        Calculated 74.96        9.78   9.71                                           Found      74.99        9.83   9.27                                           ______________________________________                                    

EXAMPLE 271-[2-(4-Fluorobenzamido)eth-1-yl]-4-(3,4-dihydro-7-methoxynaphth-1-yl)piperidinehydrochloride

The expected product is obtained in the form of the base using thecompound from Example 25 and treating it in accordance with theprocedure described in Stage B of Example 5. The base is converted tothe corresponding hydrochloride by treatment with an alcoholic solutionof hydrogen chloride.

Yield: 65%

Melting point: 250° C.

    ______________________________________                                        Elementary microanalysis:                                                               C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  67.48  6.80       6.30 7.97                                       Found       67.36  6.78       6.23 7.95                                       ______________________________________                                    

EXAMPLE 281-[2-(4-Fluorobenzamido)eth-1-yl]-4-(1,2,3,4-tetrahydro-7-methoxynaphth-1-yl)piperidinehydrochloride

The expected product is obtained in the form of the base using thecompound from Example 26 and treating it in accordance with theprocedure described in Stage B of Example 5. The base is converted tothe corresponding hydrochloride by treatment with an alcoholic solutionof hydrogen chloride.

Yield: 42%

Melting point: 204° C.

    ______________________________________                                        Elementary microanalysis:                                                               C %  H %        N %    Cl %                                         ______________________________________                                        Calculated  67.18  7.22       6.27 7.93                                       Found       67.36  7.24       6.42 7.87                                       ______________________________________                                    

EXAMPLE 29 1-Benzyl-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine

64 mmoles of the compound obtained in Stage B of Example 13 are refluxedin 220 ml of anhydrous ethanol in the presence of 19 g of o-chloraniland 8.5 ml of a 7.6 N ethanolic hydrochloric acid solution.

After evaporation, the residue is taken up in water, the whole isbrought to pH 10 and filtered through celite and the filtrate isextracted with dichloromethane.

The expected product is obtained after drying and evaporating off thesolvents and is purified by chromatography on silica (elution solvent:dichloromethane/ methanol/aqueous ammonia 99:1:0.1).

Yield: 70%

EXAMPLE 30 3-[7-Methoxynaphth-1-yl)methyl]pyrrolidine

The expected product is obtained by catalytic hydrogenation of thecompound from Example 29° at 60° C. in ethanol in the presence of 1.5 gof palladium-on-charcoal.

Yield: 85%

EXAMPLE 31 1-Cyanomethyl-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine

The expected product is obtained using the compound from Example 30 andtreating it in accordance with the procedure described in Example 4without conversion to the hydrochloride.

Yield: 95%

EXAMPLE 321-(2-Aminoeth-1-yl)-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine

The expected product is obtained using the compound from Example 31 andtreating it in accordance with the procedure described in Stage A ofExample 5.

Yield: 65%

EXAMPLE 33 1-[2-(4-Fluorobenzamido)eth-1-yl]-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine

The expected product is obtained using the compound from Example 32 andtreating it in accordance with the procedure described in Stage B ofExample 5.

Yield: 80%

Melting point: >260° C.

    ______________________________________                                        Elementary microanalysis:                                                              C %        H %    N %                                                ______________________________________                                        Calculated 65.31        5.89   5.64                                           Found      64.99        5.72   5.99                                           ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________     ##STR26##                                                                                                                       NMR SPECTRUM               EX-                                                (Solvent)                  AMPLE                                              s = salt                   No.  R.sub.1       A    B        R.sub.2           b = base                   __________________________________________________________________________     1                                                                                  ##STR27##                                                                                        ##STR28##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2.75ppm m 2H; 2.95ppm                                                         s 3H; 3.5ppm m 2H;                                                            3.95 ppm m 2H; 5.75ppm                                                        m 1H; 7.35ppm dd 1H;                                                          7.55 ppm m 3H; 7.9ppm                                                         d 1H; 8ppm m 1H; 8.05                                                         ppm m 1H; 9.5-10.5ppm                                                         1H (exchangeable)           2                                                                                  ##STR29##                                                                                        ##STR30##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (DMSO-d.sub.6 ) s                                                             2-2.2ppm m 4H; 2.8ppm                                                         s 3H; 3.3ppm m 2H; 3.6                                                        pm m 2H; 3.7ppm m 1H;                                                         7.3-7.7ppm m +d 3H+1H;                                                        7.85ppm d 1H; 7.95ppm                                                         dd 1H; 8.2ppm dd 1H;                                                          9.2-10.2 ppm 1H                                                               exchangeable                3                                                                                  ##STR31##                                                                                        ##STR32##                                                                             H                 .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              1.9-2.15ppm m 4H; 3.1-                                                        .6ppm m 4H; 3.8ppm m                                                          1H; 7.3-7.65ppm m+t+d                                                         2H+1H+1H; 7.8ppm d 1H;                                                        7.95ppm m 1H; 8.3ppm m                                                        1H; 8.4-9 ppm 1H                                                              exchangeable                4                                                                                  ##STR33##                                                                                        ##STR34##                                                                             CH.sub.2 CN       .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2-2.4ppm m 4H; 3.2-3.9                                                        pm m+m+m 1H+2H+2H;                                                            4.6ppm s 2H;                                                                  7.25-7.65ppm m+d                                                              3H+1H; 7.8ppm d 1H;                                                           7.9ppm dd 1H; 8.25ppm                                                         dd 1H                       5                                                                                  ##STR35##                                                                                        ##STR36##                                                                              ##STR37##        .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              1.8-2.4ppm m 4H; 3-3.5                                                        pm m 4H; 3.5-4ppm m                                                           5H; 7.2-7.7ppm m+m+t                                                          3H+1H+2H; 7.8ppm d 1H;                                                        7.85-8.15 ppm dd+m                                                            2H+1H; 8.2 ppm d 1H;                                                          8.8-9.3ppm 1H                                                                 exchangeable; 10.4-                                                           10.7ppm                                                                       1H exchangeable             6                                                                                  ##STR38##                                                                                        ##STR39##                                                                              ##STR40##        .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2.5-2.7ppm m 1H; 2.9-                                                         3.2ppm m 1H; 3.3-3.6                                                          ppm m+m 2H; 3.7-4.05                                                          ppm m+t 2H+2H; 4.2 ppm                                                        m 1H; 5.75ppm m  1H;                                                          7.25-7.40ppm m 3H;                                                            7.45-7.60ppm m 3H;                                                            7.8- 8.0ppm m+m 1H+1H;                                                        .05-8.3ppm m+dd 1H+2H;                                                        9.15ppm                                                                       1H exchangeable;                                                              11-11.4 ppm 1H                                                                exchangeable                7                                                                                  ##STR41##                                                                                        ##STR42##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              3.0ppm m+s 5H; 3.4-                                                           3.75ppm m 2H; 4.0-4.2                                                         ppm m 2H; 6.8ppm m 1H;                                                        7.9ppm m 1H; 8.05 ppm                                                         m 1H; 8.25ppm d 1H                                                            8.3ppm m 1H; 9.1 ppm d                                                        1H; 9.5ppm d 1H; 5.5-7                                                        1H exchangeable;                                                              9.5-10.5ppm 1H                                                                exchangeable                8                                                                                  ##STR43##                                                                                        ##STR44##                                                                             H                 .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2.9ppm m 2H; 3.4-3.75                                                         ppm m 2H; 4.0-4.2ppm m                                                        2H; 6.8ppm m 1H; 7.9                                                          ppm m 1H; 8.05ppm m                                                           1H; 8.25ppm d 1H; 8.3                                                         ppm m 1H; 9.1ppm d 1H;                                                        9.5ppm d 1H; 5.5- 7 1H                                                        exchangeable; 9.5-                                                            10.5ppm 1H                                                                    exchangeable                9                                                                                  ##STR45##                                                                                        ##STR46##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2.10ppm m 2H; 2.25ppm                                                          2H; 2.85ppm s 3H;                                                            3.20ppm m 2H; 3.30ppm                                                          1H; 3.60ppm m 2H;                                                            7.95ppm m 1H; 8.10ppm                                                         m 1H; 8.25ppm d 1H;                                                           8.35ppm d 1H; 9.00ppm                                                         d 1H; 9.30ppm d 1H;                                                           1.7-4ppm 1H ex-                                                               changeable; 9-10.2ppm                                                         1H exchangeable            10                                                                                  ##STR47##                                                                                        ##STR48##                                                                             H                 .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              2.05ppm m 2H; 2.25ppm                                                         m 2H; 3.15ppm m 2H;                                                           3.35ppm m 1H; 3.50ppm                                                         m 2H; 7.95ppm m 1H;                                                           8.10ppm m 1H; 8.25ppm                                                         d 1H; 8.35ppm d 1H;                                                           9.15ppm d 1H; 9.30ppm                                                         d 1H; 5.5-9ppm 2H                                                             exchangeable               11                                                                                  ##STR49##                                                                                        ##STR50##                                                                             CH.sub.2 CN       .sup.1 H NMR (D.sub.2                                                         O) s 2.1- 2.4ppm m 2H;                                                        2.45ppm m 2H;                                                                 3.35-3.6ppm m 1H;                                                             3.45ppm m 2H; 3.85 ppm                                                        m 2H; 4.55ppm s 2H;                                                           7.85-8.3ppm d+d+t+t                                                           1H+1H+1H+1H; 9.10 ppm                                                         d 1H; 9.15ppm d 1H         12                                                                                  ##STR51##                                                                                        ##STR52##                                                                              ##STR53##        .sup.1 H NMR                                                                  (DMSO-d.sub.6) s 2.1-                                                         2.4ppm m 4H; 3.05-3.50                                                        pm m 5H; 3.6-3.9ppm m                                                         4H; 7.3ppm t 2H; 7.90                                                         ppm td 1H; 7.95-8.15                                                          ppm m 3H; 8.3ppm m                                                            2H; 8.85ppm d 1H; 9.1                                                         ppm 1H exchangeable;                                                          9.2ppm d 1H; 10.7-11.0                                                        pm 1H exchangeable         13                                                                                  ##STR54##    CH.sub.2                                                                            ##STR55##                                                                              ##STR56##        .sup.1 H NMR                                                                  (CDCl.sub.3) b 1.55                                                           ppm m 1H; 2.0ppm m 2H;                                                        2.25ppm m 2H; 2.6-                                                            2.3ppm m 5H; 2.7 ppm t                                                        2H; 2.8ppm m 1H;                                                              3.7-3.5ppm 2d 2H; 3.8                                                         ppm s 3H; 5.85ppm t                                                           1H; 6.6ppm dd 1H;                                                             6.8ppm d 1H; 7.05ppm d                                                        1H; 7.4- 7.2m 5H           14                                                                                  ##STR57##    CH                                                                                  ##STR58##                                                                              ##STR59##        .sup.1 H NMR                                                                  (CDCl.sub.3) b 1.55ppm                                                        m 1H; 1.8ppm m 1H;                                                            2ppm m 1H; 2.6- 2.3ppm                                                        m+t+m 2H+2H+2H; 2.9ppm                                                        t 2H; 3.2ppm m 1H;                                                            3.7- 3.5ppm 2d 2H;                                                            3.8ppm s 3H; 5.95ppm                                                          dd 1H; 6.75 ppm dd 1H;                                                        6.95ppm d 1H; 7.15ppm                                                         d 1H; 7.4- 7.2ppm m                                                           5H                         15                                                                                  ##STR60##                                                                                        ##STR61##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (CDCl.sub.3) b 1.6 ppm                                                        m 2H; 1.85ppm m 2H;                                                           2.1-2.2ppm m 4H;                                                              2.3ppm s 3H; 2.45ppm m                                                        H; 2.65ppm m 2H; 3.00                                                         ppm m 2H; 3.8ppm s 3H;                                                        .9ppm m 1H; 6.7ppm dd                                                         1H; 6.8ppm d 1H; 7.1                                                          ppm d 1H                   16                                                                                  ##STR62##                                                                                        ##STR63##                                                                             CH.sub.3          .sup.1 H NMR                                                                  (CDCl.sub.3) b                                                                1.8-2.1ppm m 4H; 2.2                                                          ppm m 2H; 2.4ppm s 3H;                                                        -3.3ppm m 3H; 3.95ppm                                                         s 3H; 7.15ppm dd 1H;                                                          7.2-7.45ppm m 3H; 7.9                                                         ppm d 1H; 7.8ppm d 1H      17                                                                                  ##STR64##                                                                                        ##STR65##                                                                             H                 .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              1.8-2.1ppm m 4H; 3.1-                                                         3.5ppm m 4H; 3.5-3.8                                                          ppm m 1H; 3.9ppm s 3H;                                                        .2ppm dd 1H; 7.3 ppm m                                                        2H; 7.45ppm d 1H;                                                             7.75ppm m 1H; 7.85 ppm                                                        d 1H; 9-9.5ppm 2H                                                             exchangeable               18                                                                                  ##STR66##                                                                                        ##STR67##                                                                              ##STR68##        .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              1.9-2.4ppm m 4H; 3.1-                                                         3.9ppm m 9H; 3.9ppm s                                                         3H; 7.1-7.4ppm                                                                m+t+d+dd 2H+1H+1H+1H;                                                         7.45 ppm d 1H; 7.7ppm                                                         m 1H; 7.85ppm d 1H;                                                           8.05 ppm dd 2H;                                                               9-10.7ppm 2H                                                                  exchangeable               19                                                                                  ##STR69##                                                                                        ##STR70##                                                                             H                 .sup.1 H NMR                                                                  (DMSO-d.sub.6) s                                                              1.7ppm m 2H; 2.3-2.6                                                          ppm t+t 2H+2H; 2.6 ppm                                                        t 2H; 2.75ppm t 2H;                                                           3.1ppm m 2H; 3.4ppm m                                                         2H; 3.75ppm s 3H; 6.65                                                        pm d 1H; 6.7ppm dd 1H;                                                        7.05ppm d 1H; 9.3 ppm                                                         1H exchangeable            20                                                                                  ##STR71##                                                                                        ##STR72##                                                                             CH.sub.2 CN       .sup.1 H NMR                                                                  (CDCl.sub.3) b 1.85ppm                                                        q 2H; 2.5ppm t 2H;                                                            2.5-2.7ppm m 8H;                                                              2.75ppm t 2H; 3.55ppm                                                         d 2H; 3.8ppm s 3H;                                                            6.7m 2H; 7.05ppm d 1H      21                                                                                  ##STR73##                                                                                        ##STR74##                                                                              ##STR75##        .sup.1 H NMR                                                                  (CDCl.sub.3) b 1.2 ppm                                                        q 2H; 2.3-2.8 ppm m                                                           14H; 3.55ppm q 2H;                                                            3.8ppm s 3H; 6.75 ppm                                                         m 2H; 7.0-7.3ppm m 3H;                                                        7.85ppm dd 2H              22                                                                                  ##STR76##                                                                                        ##STR77##                                                                              ##STR78##        .sup.1 H NMR                                                                  (CDCl.sub.3) b                                                                2.8-2.4ppm m 4H; 3.1                                                          ppm m 2H; 3.6ppm s 2H;                                                        .2ppm s 4H; 5.8ppm m                                                          1H; 6.75ppm m 3H; 7.3                                                         ppm m 5H                   23                                                                                  ##STR79##                                                                                        ##STR80##                                                                              ##STR81##        .sup.1 H NMR                                                                  (CDCl.sub.3) b                                                                2.7-3.8ppm m 6H; 3.8-                                                         4.25ppm m 4H; 4.25ppm                                                         m 4H; 5.8ppm m 1H;                                                            6.65-6.9ppm m 3H; 7.15                                                        pm t 2H; 8.2ppm dd 2H;                                                        9 and 12.2 ppm 2H                                                             exchangeable               __________________________________________________________________________

PHARMACOLOGICAL STUDY EXAMPLE 34 Evaluation of the Antihypertensiveactivity of the Compounds of the Invention

Mongrel dogs (males and females) were anesthetized with phenobarbital(30 mg/kg i.v.) and then placed under artificial respiration (Bird MarkVII respirator). The arterial pressure was measured using a catheterplaced in the abdominal aorta via the femoral artery. This catheter isconnected to a pressure cell (Statham® R₂₃ D₆) connected to a recorder.

The heart rate was measured using a Gould Biotach®.

The sympathetic nervous activity was recorded at the level of the renalnerve using a silver electrode. The amplified signal was displayed on anoscilloscope (Tektronix 5115®) and then measured in UV using a Gouldintegrator. The compounds to be examined were administeredintravenously.

The results of this study, indicated in Table II, have demonstrated thatthe compounds of the invention are more active than, or at leastcomparable with, the reference product flesinoaxan, in racemic form orin the form of an isomer (+). This isomer is the most active isomer offlesinoxan.

                                      TABLE II                                    __________________________________________________________________________                EFFECT ON THE   EFFECT ON THE                                                 ARTERIAL PRESSURE                                                                             CARDIAC RHYTHM                                                                            DOSES                                 COMPOUNDS   (mmHg)          (B/min)     μg/kg                              __________________________________________________________________________    Flesinoxan (+) Isomer                                                                      ##STR82##                                                                                     ##STR83##   10  30 100                           Flesinoxan racemic                                                                         ##STR84##                                                                                     ##STR85##   10  30 100 300                       Compounds of the invention                                                                 ##STR86##                                                                                     ##STR87##   3-10 10-30 30-100                    __________________________________________________________________________

With regard to the sympathetic nervous activity, the results obtainedwith the compound of Example 18 after i.v. administration of a dose of30 μg/kg are given in FIG. 1.

EXAMPLE 35 Evaluation of the Affinity for 5-HT_(1A) Receptors

Hippocampus tissue obtained from decapitated Wistar rats was used forthe studies. The animals were sacrificed 48 hours before the experimentand the isolated tissues were stored at -86° C. For preparation of themembranes, the tissues were then homogenized using 20 volumes of a 50 mMTris HCl buffer solution (pH =7.7, adjusted using NH₄ Cl at 25° C.) forone volume of tissue, at a temperature close to 0° C., using a Polytron®homogenizer, and the whole was then centrifuged. (35,000 g×20 min at 4°C.). The pellet thus obtained was suspended in 100 volumes of anincubation buffer solution. (60 mM Tris, 10 μM pargyline, 4 mM CaCl₂ and0.1% (wt/v) ascorbic acid; pH adjusted to 7.7 with 5N HCl). Thecompounds to be examined were also diluted in the incubation buffer andthe solutions were then prepared by adding 100 μl of a solution of thecompound to be examined and 100 μl of a solution of [3H] 8-OH-DPAT C=0.4 nM (specific radioactivity =205 Ci/mmol) to 12×75 mm glass tubes.The non-specific binding was determined using a 10 μM5-hydroxytryptamine solution and corresponds to 5-10% of the totalbinding.

The tubes were incubated for 30 min at 37° C. and the solutions werethen filtered through GF/B glass fiber filters treated with 0.1% ofpolyethyleneimine (Whatman®). The filters were rinsed twice with 5 ml ofthe incubation buffer solution and were then placed in ampoules to which4.5 ml of "Picofluor scintillation fluid"® (Packard) had been added. Theradioactivity was determined using external standards.

The pKi were evaluated using the Cheung-Prusoff equation:

    -log (IC.sub.50 /[1+[3H]8-OH-DPAT]/Kd).

The compounds of the invention have a high affinity for the 5-HT_(1A)sites. The pKi of the compounds of the invention are of the order of9.02 moles/liter.

    ______________________________________                                        PHARMACEUTICAL PREPARATION                                                    EXAMPLE 36                                                                    Capsules containing 1 mg of 1-[2-(4-fluorobenzamido)eth-1-yl]-                4-(7-methoxynaphth-1-yl)piperidine hydrochloride [F.A.E.M.N.P]                ______________________________________                                        F.A.E.M.N.P.           1 mg                                                   Corn starch            15 mg                                                  Lactose                25 mg                                                  Talc                   5 mg                                                   ______________________________________                                    

We claim:
 1. A compound selected from those of the formula I: ##STR88##in which R₁ represents a naphthyl radical, of formula y₁ : ##STR89## adihydronaphthyl radical, of formula y₂ : ##STR90## a tetrahydronaphthylradical of formula y₃ : ##STR91## (in which formulae R₃ representshydrogen, halogen, alkyl having 1 to 6 carbon atoms inclusive hydroxyl,or an alkoxy having 1 to 6 carbon atoms inclusive),A represents a singlebond, a double bond (on condition, however, that R₁ represents atetrahydronaphthyl radical), R₂ represents: an aminoalkyl having 1 to 6carbon atoms inclusive, cyanoalkyl having 1 to 6 carbon atoms inclusiveor a radical of formula w₁ : ##STR92## in which: n is 1-6 inclusive andR₄ represents hydrogen, halogen, alkyl having 1 to 6 carbon atomsinclusive or alkoxy having 1 to 6 carbon atoms, its possiblestereoisomers, and its addition salts with a pharmaceutically-acceptableacid.
 2. The compound as claimed in claim 1 which is selected from1-[2-(4-fluorobenzamido)eth-1-yl]-1-yl]-4-(7-methoxynaphth-1-yl)piperidine, and its addition salts with a pharmaceutically-acceptableacid.
 3. A method for treating a living animal or human afflicted with ahypertensive condition requiring an agonist for 5-HT_(1A) receptorscomprising the step of administering to the said living animal or humanan amount of a compound of claim 1 which is effective for alleviation ofsaid condition.
 4. A method as claimed in claim 3 for treating an animalor human afflicted with hypertension.
 5. A pharmaceutical compositionuseful for treating a condition requiring a 5-HT_(1A) agonist comprisingas active principle an effective 5-HT_(1A) receptor agonistic amount ofa compound as claimed in claim 1, in combination with apharmaceutically-acceptable excipient or vehicle.
 6. The compound asclaimed in claim 1 which is selected from1-[2-(4-fluorobenamido)eth-1-yl]-4-(7-methoxynaphth-1-yl) piperidinehydrochloride.